Evaluation of serum vascular endothelial growth factor as a biomarker in Erdheim-Chester disease.
Authors: Anais Roeser, Marine Bravetti, Lida Dong, Levi Dan Azoulay, Makoto Miyara, Pascale Ghillani-Dalbin, Jean Francois Emile, Fadwa El Kouari, Frédéric Charlotte, Jean-Philippe Spano, Isabelle Brocheriou, Zahir Amoura, Fleur Cohen-Aubart, Julien Haroche
Journal: Journal of Clinical Oncology (2022)

7059 Background: Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by tissue infiltration of CD68 + , CD1a - histiocytes, derived from cells of the mononuclear phagocyte system harboring recurrent mutations in the MAPK-signaling pathway. Vascular endothelial growth factor-A, also referred as VEGF, is a major regulator of angiogenesis, implicated in cancer pathophysiology. Mutation of the RAS oncogene induce the upregulation of VEGF gene expression. We hypothesized that VEGF could play a role in ECD pathophysiology. We aimed to determine if VEGF was expressed by ECD histiocytes, to assess levels of serum VEGF (sVEGF) in ECD patients, and determine if they were associated with patient’s characteristics. Methods: We conducted a retrospective study, screening all ECD patients seen in the French National Reference Center for Histiocytoses (Pitié-Salpêtrière Hospital) from 2009 to 2019. Patients were included if they had at least one sVEGF determination. Biopsies of patients with extreme sVEGF were centrally reviewed and an immunostaining for VEGF was practiced using 2 different antibodies (F/PU483-UP and VG-1). Results: We included 248 patients in the analysis. sVEGF were high ( &gt; 500pg/mL) at first determination in 123 patients (53%), and &gt; 1000 pg/mL in 47 (19%). Median sVEGF was 843pg/mL in the high sVEGF group, 288pg/mL in the low sVEGF group. Sex, age, and BRAF status were not significantly different between the 2 groups. We analyzed 24 histological samples. Histiocytes had a VEGF staining in all samples analyzed, moderate (grade 2) in 5 and 1 cases and intense (grade 3) in 17 and 22 cases based on F/PU483-UP and VG-1 clone respectively. Control (4 biopsies of reactional sinusal histiocytoses) showed no histiocytic VEGF staining. Patients with high sVEGF had more frequently a vascular involvement (71% vs 48%, p = 0.0004) and a cardiac involvement (58% vs 41%, p = 0.008). Consecutive measurements of sVEGF were available for 183 patients (median interval: 24 months). sVEGF significantly decreased during follow-up (p &lt; 0.0001). Consecutive cardiac MRI were available for 45 patients (median interval: 48 months). All patients had cardiac involvement: 6 achieved complete response, 25 partial response, 12 were stable, and 2 progressed. Mean variation of sVEGF (∆sVEGF) of patients with complete response, partial response and stable disease were respectively - 591.3, -163.9, - 239.6 pg/mL and were significantly different from patients who progressed (mean ∆sVEGF + 555.5pg/mL). No patients in our cohort received a systemic anti-VEGF therapy for ECD or another indication. Conclusions: In our study, sVEGF was high in 53% of ECD patients, and its elevation associated with cardiac and vascular involvements. Variations of sVEGF were associated with responses of cardiac involvement under therapy. VEGF was at least partly produced by ECD histiocytes. sVEGF could help monitor cardiac involvement activity.